The human retinoid X receptors (hRXRs) consist of three identified isoforms (α, β, γ) that function as transcription promoters often in partnership with other members of a larger nuclear receptor (NR) family of transcription regulators including the thyroid receptor (TR), the vitamin D receptor (VDR), the liver X receptor (LXR), the peroxisome proliferator-activated receptor (PPAR), and the retinoic acid receptor (RAR). While 9-cis-retinoic acid (9-cis-RA) and docosahexaenoic acid (DHA) have been shown to bind to hRXRs and promote RXR element (RXRE) regulated transcription (i.e. function as RXR agonists), it is still unclear if RXR has a bona fide endogenous molecular ligand. RXR has been described as the central NR regulator, because it often plays a critical role, either as a permissive or non-permissive partner, in heterodimer complexes that must be formed with the other NRs to regulate their respective response elements.
Recent studies have identified several RXR-selective-binding molecular ligands (rexinoids) that can modulate not only RXRE regulated transcription but also the heterodimer regulated transcription of other NRs. For instance, RXR is a subordinate partner in the RXR-RAR heterodimer, otherwise referred to as a non-permissive heterodimer, since transcription is not promoted in the RAR unliganded (apo-RAR) heterodimer with RXR. Additionally, the RXR-TR heterodimer is non-permissive. In contrast to these non-permissive heterodimers, permissive heterodimers such as RXR-PPAR allow transcription to be promoted in the presence of either RXR or PPAR agonists. The RXR-LXR heterodimer is also permissive. Hence, there is enormous potential for RXR agonists to activate or repress various biological pathways and effect therapeutic results for various conditions that would benefit from activation or repression of a specific pathway.
Bexarotene has been used to treat cutaneous T cell lymphoma. Bexarotene has also been shown to be useful for treatment of Alzheimer's Disease (AD). However, bexarotene treatment results in untoward side effects, possibly due to its nonspecific nature of binding RXR in several states, including the RXR-RXR homodimer form as well as RXR heterodimer forms.
McFarland, K., et al, ACS Chem. Neurosci., 2013, 4(11), 1430-1438 treated a rat model of Parkinson's disease (PD) with bexarotene and noted marked improvement in the PD symptoms. Specifically the bexarotene restored dopamine cells and natural behavior in the PD model. As importantly, the bexarotene dose that accomplished this was quite low, alleviating some side effects. The researchers demonstrated that these symptoms were alleviated by bexarotene binding to RXR and its heterodimerizing with another nuclear recpetor called Nurr1.
PD is a chronic, debilitating disorder in which the neurons of the central nervous system degenerate over time. Specifically the dopamine secreting cells of the midbrain slowly die off, leaving the patient with a wide range of symptoms due to the lack of dopamine. Early symptoms include shaking, off balance gait, and slowless of muscles. Over time, symptoms worsen and additional symptoms including dementia and/or depression can develop. Treatments include dopamine agonists, given to try to ameliorate the effect of loss of dopamine in the system.
The compound 9c-UAB30 has been reported to be effective as a retinoid-X-receptor (RXR) agonist with reduced side effect profiles. See, Brouilette, W. J.; Muccio, D. D. PCT Int. Appl. (1999), WO 9951562; Atigadda, V. R. et al., J. Med. Chem. 2003, 46, 3766-3769; Grubbs, C. J., et al., Cancer Letters 2003, 201, 17-24; Brouillette, W. J., et al., PCT Int. Appl. (2006), WO 2006036394; Hansen, N. J., et al., International Journal of Oncology 2007, 30, 641-650; Gorman, G. S., et al., Drug Metabolism and Disposition 2007, 35, 1157-1164; Kapetanovic, I. M., et al., International Journal of Toxicology 2010, 29, 157-164; Kolesar, J. M., et al., Cancer Prevention Research 2010, 3, 1565-1570; Lindeblad, M., et al., Drug and Chemical Toxicology 2011, 34, 300-310; Whitworth, J. M., et al., Gynecologic Oncology 2012, 125, 226-230; Brouillette, W. J., et al., (2013), U.S. Pat. No. 8,475,775.

Additionally compound 100 has been reported to be effective as a retinoid-X-receptor (RXR) agonist with potential as a therapeutic agent for treating for human cancers (Atigadda, V. R. et al., J. Med. Chem. 2014, 57, 5370-5380).

Currently there is a need for additional chemical agents that are useful for treating conditions including Alzheimer's disease, Parkinson's disease, diabetes, cancer, and psychotic disorders such as schizophrenia.